Our recent studies of DNA virus infected cells suggest that the early genes of DNA viruses impart specific levels of susceptibility or resistance to cellular immune rejection to these cells. In DNA virus transformed cells, the susceptibility-resistance phenotype may determine the tumor inducing capacity of those cells. In in vitro assays the susceptibility-resistance phenotype can be reflected in the ability of infected or transformed cells to be lysed by natural killer cells or activated macrophages. At this junction, the induction of the susceptibility phenotype--as expressed by hamster cells infected or transformed by adenovirus (Ad2)--appears to govern the phenotype of the affected cell; whereas, the expression of the resistant phenotype may be due to a species specific inability of certain viruses to induce susceptibility in normal cells which are inherently resistant. In support of this concept, we have found a dose-dependent correlation between the level of Ad2 early gene products expressed in transformed hamster cells and: 1) their level of susceptibility to NK cell lysis, 2) their expression of the cytoskeletal proteins - actin and fibronectin, 3) their cytomorphology. We have also developed data which suggests that the induction of susceptibility is associated with the expression of the 13S mRNA of the E1A region of the Ad2 and Ad5 genomes. As rodent cells can be immortalized by the same segment the cDNA 5' terminus of 13S of the Ad2 and Ad5 genomes that fail to induce susceptibility and as this region of the genome is not known to induce virus-specific cell surface proteins, cell immortalization towards neoplasia is an event independent of the induction of susceptibility to lysis by immunologically non-specific host effector cells. In addition, susceptibility to lysis by effector cells may not be associated with the presence of virus-specific proteins on the surface of susceptible cells.